LAUSR

Blocking the nitrosylation of GAPDH may reduce amyloid-induced tau toxicity in the brain and slow the progression of Alzheimer’s disease. Nitrosylation links amyloid and tau pathology Amyloid-β (Aβ), tau aggregates, and nitrosative stress all contribute to the synaptic dysfunction and neurodegeneration associated with the pathology of Alzheimer’s disease. Sen et al. found that the three are functionally linked; Aβ-induced tau acetylation and aggregation by stimulating the enzyme that produces nitric oxide (NO). An increased amount of NO in cortical neurons promoted the nitrosylation of the glycolytic enzyme GAPDH and, subsequently, the activation of the acetylase p300 and inactivation of SIRT1, which together enhanced the pathological acetylation of tau. Treating mice with the GAPDH nitrosylation inhibitor omigapil, which is currently being tested to treat congenital muscular dystrophy, prevented amyloid-induced τ acetylation, memory impairment, and locomotor dysfunction, suggesting that this drug might be explored to treat patients with AD. Acetylation of the microtubule-associated protein tau promotes its polymerization into neurofibrillary tangles that are implicated in the pathology of Alzheimer’s disease (AD). The gaseous neurotransmitter nitric oxide (NO) regulates cell signaling through the nitrosylation of proteins. We found that NO production and tau acetylation at Lys280 occurred in the brain tissue in mice and in cultured mouse cortical neurons in response to exposure to amyloid-β1–42 (Aβ1–42), a peptide that is also implicated in AD. An increased abundance of NO facilitated the S-nitrosylation (SNO) of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). S-nitrosylated GAPDH (GAPDH-SNO) promoted the acetylation and activation of the acetyltransferase p300 and facilitated the nitrosylation and inactivation of the deacetylase sirtuin 1 (SIRT1). The abundance of GAPDH-SNO was increased in postmortem brain samples from AD patients. Preventing the increase in GAPDH-SNO abundance in both cultured neurons and mice, either by overexpression of the nitrosylation mutant of GAPDH (GAPDH C150S) or by treatment with the GAPDH nitrosylation inhibitor CGP3466B (also known as omigapil), abrogated Aβ1–42–induced tau acetylation, memory impairment, and locomotor dysfunction in mice, suggesting that this drug might be repurposed to treat patients with AD.